Summary of Work: Transgenic mice that express elevated levels of IFN-[unreadable] mRNA and protein were produced by inserting murine IFN-gamma genomic DNA containing an immunoglobulin lambda chain enhancer in the first intron. IFN-[unreadable] transgenic mice show a pronounced reduction in B-lineage cells in the bone marrow, spleen and lymph nodes. All bone marrow B220+ cells are arrested in their development as CD43+ pro-B cells. The immunoglobulin heavy chain locus has undergone DH to JH rearrangement but no V to D rearrangements were detected. PCR amplification studies conducted on whole bone marrow RNA failed to detect the presence of transcripts from genes expressed early in B cell development such as V-preB, lambda-5, Ig-alpha and Ig-delta. Rag-1 and Rag-2 transcripts were also undetectable. TdT transcripts were detected. Addition studies are being conducted on RNA purified from enriched populations of B220+ bone marrow cells in order to analyze a more specific set of transcripts and resolve the question of Rag gene expression. Injection of IFN-gamma transgenic mice with anti-IFN-gamma antibody, anti-IFN-gamma receptor antibody, or cyclosporin A, alone or in combination, did not reverse the phenotypic effects of the IFN- gamma transgene. The IFN-gamma transgenic mice were crossed to bcl-2 transgenic mice to determine whether or not bcl- 2 could rescue B cell development in these mice. The presence of bcl-2 had no effect, thus, these cells remained developmentally blocked at the pro-b cell stage of differentiation. Mice expressing the mukappa anti-phosphocholine transgenes in the presence of the IFN-gamma transgene also failed to develop sIgM+ B cells. This IFN-gamma mediated defect thus appears to be due to expression of IFN-gamma within the B cell progenitors. Flow cytometric analysis of these arrested progenitors shows that the overall number is greatly reduced and arrest appears to take place at the Hardy B stage of Pro-B cell development with few BP-1+ B220+ HSA+ cells developing.